Adenosine receptors are subdivided into four general subtypes; A1, A2A, A2B, and A3, all of which modulate important physiological processes ((G. L. Stiles, K. A. Jacobson, and M. F. Jarvis, Wiley-Liss: New York, (1997); pp 29–37; V. Ralevic; G. Burnstock, G. Pharmacol. Rev. (1998) Vol. 50, 413–492). For example, stimulation of the A1 adenosine receptors shortens the duration and decreases the amplitude of the action potential of AV nodal cells, and hence prolongs the refractory period of the AV nodal cell. Thus, stimulation of A1 receptors provides a method of treating supraventricular tachycardias, including termination of nodal re-entrant tachycardias, and control of ventricular rate during atrial fibrillation and flutter. Stimulation of cell surface A2A receptors produces dilation of the coronary resistance vessels, which phenomenon is useful for pharmacological stress imaging. A2B receptors have been implicated in mast cell activation, asthma, vasodilation, regulation of cell growth, intestinal function, and modulation of neurosecretion (See Adenosine A2B Receptors as Therapeutic Targets, Drug Dev Res 45:198; Feoktistov et al., Trends Pharmacol Sci 19:148–153). A3 adenosine receptors modulate cell proliferation processes. In particular, compounds that are A3 receptor agonists have utility in the therapeutic and/or prophylactic treatment of cancer, cardiac disease, infertility, kidney disease, and CNS disorders.
Recently, A2A receptors have been demonstrated to be involved in CNS mediated effects such as movement, and compounds that act as agonists of the A2A receptor produce symptoms of “movement disorders.” Movement disorders are exemplified by Parkinson's Disease, which is characterized by symptoms of muscle rigidity, tremor and paucity of movement. The symptoms of Parkinson's Disease are due to the degeneration and destruction of the dopaminergic neurones in the substantia nigra, which causes a loss of dopamine, a neurotransmitter that regulates movement. The decrease in dopamine leads to a relative excess of acetylcholine, which produces the tremor associated with Parkinsons Disease. Treatment strategies, therefore, have been aimed at stimulating dopamine levels and/or inhibiting the action of acetylcholine. These treatments have not been effective in long term control of the disorder or prevention of its progression.
It has been found that compounds that antagonize the effects of adenosine at the A2A receptor mitigate the effect of movement disorders. For example, theophylline, which has an antagonistic effect at the A2A receptor, provides significant improvement of symptoms in Parkinson's patients. KF 17837, a selective adenosine A2A receptor antagonist, ameliorates experimentally induced cataleptic responses.
A2A receptor antagonists also possess neuroprotective properties. A2A antagonists have been shown to block kainate-induced excitotoxicity in the hippocampus, to reduce ischemia-evoked glutamate and aspartate release from the cortex, and to reduce the extent of the ischemia-induced injury in rats and gerbils. Further evidence for A2A receptor mediated neuroprotection arises from studies demonstrating that both cerebral infarct size and neurological deficits following transient ischemia are attenuated in A2A receptor knockout mice. These data are in line with the view that adenosine confers neuroprotective effects in part by inhibiting glutamate release. These findings are significant because glutamate excitotoxicity has been implicated in the pathogenesis of Parkinson's diseases, and it has been speculated that a blockade or reduction in glutamteric neurotransmission may arrest neurodegeneration in Parkinson's. Thus, A2A receptor antagonists have a dual role in treating Parkinson's Disease, by effectively slowing further neurodegeneration while providing symptomatic relief with fewer side effects compared to existing therapies.
As previously mentioned, stimulation of A2A adenosine receptors produces dilation of the coronary resistance vessels. Although this phenomenon is useful for pharmacological stress imaging, it is not favorable for patients who have elevated endogenous adenosine, because excessive vasodilation potentially leads to coronary steal. The phenomenon of coronary steal can cause tissue damage, because ischemia may be produced in the vascular beds fed by the artery that has lowered blood flow due to the more favorable vasodilation of healthy adjoining arteries. Accordingly, an A2A antagonist will prevent the phenomenon of coronary steal.
Accordingly, it is desired to provide compounds that are potent A2A antagonists, useful in the treatment of various disease states related to modulation of the A2A receptor, in particular cardiovascular diseases such as tissue damage caused by ischemia, and CNS-related diseases such as Parkinson's Disease. Preferably, the compounds would be selective for the A2A receptor, thus avoiding side effects caused by interaction with other adenosine receptors.